Novel thiazole-based compound and inhibitor of t-type calcium channel containing the same

ABSTRACT

The present invention relates to novel thiazole-based compounds and T-type calcium channel inhibitors containing the compound. The T-type calcium channel inhibitor of the present invention is useful as a treating agent for disease associated with overexpression of T-type calcium channel.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to and the benefit of Korean Patent Application No. 2006-0074201 filed on Aug. 7, 2006, which is hereby incorporated by reference for all purposes as if fully set forth herein.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

The present invention relates to thiazole-based compounds represented by following Chemical Formula 1, and T-type calcium channel inhibitors containing the compound. The T-type calcium channel inhibitors according to the present invention are useful as a treating agent of diseases associated with over-expression of T-type calcium channel.

(b) Description of the Related Art

T-type calcium channel is a kind of voltage-dependent calcium channels, which plays an important role in regulating intracellular calcium level at depolarization. As coding genes for the voltage-dependent calcium channels, ten (10) genes have been found, which may be classified into two (2) families, a high voltage activated (HVA) family and a low voltage activated (LVA) family, according to the intensity of the activating voltage. The voltage-dependent calcium channels may be classified into three (3) families, L-type channels (Cav1), P/Q-type and N-type (nervous unit) channels (Cav2), and T-type channels, wherein the L-type channels, and P/Q-type and N-type channels belong to the high voltage activated family, and the T-type channels belong to the low voltage activated family (Ertel et al., 2000).

T-type calcium channel is characterized by low-voltage activated calcium current, rapid activation and slow inactivation. Up to date, as coding genes for the T-type calcium channel, three (3) genes have been identified, and named as α1G (Cav3.1), α1H (Cav3.2), and α1I (Cav3.3), respectively (Cribbs et al., 1998; Perez-Reyes et al., 1998; Klugbauer et al., 1999; Lee et al., 1999; Monteil et al., 2000). The T-type calcium channels may be expressed in whole body, such as a nervous tissue, heart, kidney, smooth muscle, and endocrine organ. The T-type calcium channels have been found to have the functions to regulate bursting firing of nervous cells (Huguenard, J. R. et al., Annu. Rev. Physiol. 1996, 58, 329-348), heart pacemaker activity (Zhou, Z et al., J. Mol. Cell. Cardiol. 1994, 26, 1211-1219), secretion of hormone aldosterone (Rossier, M. F. et al., Endocrinology 1996, 137, 4817-4826) and fertilization (Arnoult, C. et al., Proc. Natl. Acad. Sci. 1996, 93, 13004-13009). Recently, it has been revealed that the T-type calcium channels are also associated with pain signaling (Ikeda, H. et al., Science, 2003, 299, 1237-1240).

The relationship between the expression of the T-type calcium channel and various diseases has been found. The expression of the T-type calcium channel in brain is found to be associated with nociception and repetitive low threshold firing. Especially, a recent study reported a direct relationship between the expression of the T-type calcium channel and pain using a knock-out mouse wherein T-type calcium channel is deleted (Bourinet E. et al., EMBO, 2005, 24, 315-324; Shin, H. S. et al., Science, 2003, 302, 117-119). In addition, the T-type calcium channel is associated with epilepsy. Absent seizure, which is a type of epilepsy, is caused by over-activation of T-type calcium channel in brain (Tsakiridou E et al., J. Neurosci. 1995, 15, 3110-3117). Ethosuccimide is an inhibitor against T-type calcium channel, and has been used in treatment of absence seizure. T-type calcium channel is commonly expressed in heart and smooth muscle, and thus, the inhibitors thereof can be also useful in treatment of hypertension, angina pectoris, and arrhythmia. Recently, it has been found that the T-type calcium channel is associated with the invasion and metathesis of cancer cells, and thus, the inhibitors thereof may be useful as anticancer drugs (Petty, H. R. et al., US 20060003020A1; McCalmont, W. F. et al, Bioorg. Med. Chem. Lett. 2004, 14, 3691-3695).

The exemplary inhibitor against the T-type calcium channel is miberefradil (Posicor®) developed by Roche. Mibefradil, which is a non-dihydropyridine calcium channel inhibitor, obtained FDA approval as a treating drug against hypertension and angina pectoris in 1997. However, Mibefradil has been voluntarily removed since 1999 because of its side effect caused by drug-drug interaction by CYP 3A4 enzyme inhibition.

Therefore, efficient T-type calcium channel inhibitors have not been developed yet. In view of the effects of T-type calcium channel on nerve, pain, epilepsy, hypertension, angina pectoris, heart muscle diseases, blood vessels, cancer metathesis, it has been required to develop efficient T-type calcium channel inhibitors capable of preventing and treating various T-type calcium channel associated diseases by inhibiting the over-expression and over-activation of T-type calcium channel.

SUMMARY OF THE INVENTION

To satisfy the above request, the object of the present invention is to provide novel thiazole-based compounds having T-type calcium channel inhibiting activity, and T-type calcium channel inhibitors containing the compound.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A more complete appreciation of the invention, and many of the attendant advantages thereof, will be readily apparent as the same becomes better understood by reference to the following detailed description.

The present invention relates to thiazole-based compounds represented by following Chemical Formula 1, and T-type calcium channel inhibitors containing the thiazole-based compound. The T-type calcium channel inhibitors according to the present invention may be useful in treatment of various diseases associated with the over-expression of T-type calcium channel.

At first, the present invention provides thiazole-based compounds represented by following Chemical Formula 1:

wherein

R1 is

R and R′ are the same or different for each other, and independently selected from the group consisting of hydrogen atom, halogen atom, C1-C5 alkyl, alkyloxy, phenyloxy, nitro, cyano, alkoxycarbonyl, and C3-C6 cycloalkyl,

n is 0, 1, or 2,

R2 is

X is halogen atom.

In a preferable embodiment of the present invention, the compounds may be represented by following Chemical Formula 2 or 3:

wherein R, R′, X and n are the same as defined above.

In an embodiment of the present invention, the thiazole-based compound may be selected from the group consisting of the following compounds:

-   [2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2-fluoro-5-nitrophenyl)acetamide     hydrochloride]; -   N-(2-chloro-4-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   N-(3-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-fluorophenyl)acetamide     hydrochloride; -   N-(5-chloro-2-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   N-(4-chloro-2-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   N-(2-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-p-tolylacetamide     hydrochloride; -   N-(4-cyanophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-phenylacetamide     hydrochloride; -   N-(4-bromophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3-fluoro-4-methoxyphenyl)acetamide     hydrochloride; -   N-(4-chlorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3,5-dichlorophenyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-ethylphenyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methylbenzyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methylphenethyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3,4-difluorobenzyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-fluorophenethyl)acetamide     hydrochloride; -   N-(2-bromo-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   N-(4-ethoxyphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-isopropylphenyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-nitrophenyl)acetamide     hydrochloride; -   N-(4-decylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   ethyl     3-(2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamido)benzoate     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-hexylphenyl)acetamide     hydrochloride; -   N-(4-butoxyphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   ethyl     4-(2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamido)benzoate     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-hexylphenyl)acetamide     hydrochloride; -   N-(4-(cyanomethyl)phenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   N-(4-butylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-phenoxyphenyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,6-dichloro-4-(trifluoromethyl)phenyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,3,4-trifluorophenyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methoxy-2-methylphenyl)acetamide     hydrochloride; -   N-(3,5-bis(trifluoromethyl)phenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,3,5,6-tetrachlorophenyl)acetamide     hydrochloride; -   N-(3-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,6-dichloro-4-(trifluoromethoxy)phenyl)acetamide     hydrochloride; -   2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3-fluoro-4-methoxyphenyl)acetamide     hydrochloride; -   2-(4-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-yl)thiazole-2-yl)guanidine     hydrochloride; -   2-(5-(4-fluorobenzyl)-4-methylthiazole-2-yl)guanidine hydrochloride; -   2-(4-(4-chlorophenyl)thiazole-2-yl)guanidine hydrochloride; -   2-(4-(4-fluorophenyl)thiazole-2-yl)guanidine hydrochloride; -   2-(4-(2,4-difluorophenyl)thiazole-2-yl)guanidine hydrochloride; -   2-(4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)thiazole-2-yl)guanidine     hydrochloride; -   2-(4-(biphenyl-4-yl)thiazole-2-yl)guanidine hydrochloride; -   2-(4-(naphthalene-2-yl)thiazole-2-yl)guanidine hydrochloride; -   2-(4-p-tolylthiazole-2-yl)guanidine hydrobromide; -   2-(4-(4-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(2-chlorophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(2-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(4-nitrophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(2,4-dimethoxyphenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(2-fluoro-4-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(2,4-dichlorophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-phenylthiazole-2-yl)guanidine hydrobromide; -   2-(4-(4-bromophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-m-tolylthiazole-2-yl)guanidine hydrobromide; -   2-(4-(3-fluorophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(2-fluorophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(3-(trifluoromethyl)phenyl)thiazole-2-yl)guanidine     hydrobromide; -   2-(4-(3-bromophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(4-ethylphenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(3-chlorophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(4-nitrophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(3,4-dichlorophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(2,5-difluorophenyl)thiazole-2-yl)guanidine hydrobromide; -   2-(4-(3,5-bis(trifluoromethyl)phenyl)thiazole-2-yl)guanidine     hydrobromide.

The thiazole-based compounds of the present invention have excellent T-type calcium channel inhibiting activities, as shown in the experimental examples below. As described above, since the over-expression or over-activation of T-type calcium channel may cause pain, epilepsy, hypertension, angina pectoris, heart muscle disease, vascular disorder, cancer metathesis, and the like, the thiazole-based compounds of the present invention can be used in preventing or treating such diseases.

Therefore, the present invention provides a composition for inhibiting T-type calcium channel containing the thiazole-based compound represented by Chemical Formula 1, 2 or 3, or pharmaceutically acceptable salt thereof. Further, the present invention provides a composition for preventing or treating a disease selected from the group consisting of nervous disease, pain, epilepsy, hypertension, angina pectoris, heart muscle disease, vascular disorder, and cancer.

The amount of the thiazole-based compound contained in the composition according to the present invention may be approximately 0.1 to 99 wt %, but more preferably, properly controlled according to its usage. Further, the administration dosage may be determined considering age, sexuality and condition of patient, absorption and inactivation rates in the body of the active ingredient, and co-administered drugs. For example, the dosage of the composition may be 2 mg/kg (body weight) to 500 mg/kg based on the active ingredient.

The composition according to the present invention may contain the thiazole-based compound with or without other pharmaceutically acceptable drugs, carriers, or excipients. The carriers and excipients used in the present invention may be properly selected depending on the intended formulation type of the composition, for example, including conventional diluents, fillers, expanders, wetting agents, disintegrants, and/or surfactants. Representative diluents or excipients may include water, dextrin, calcium carbonate, lactose, propylene glycol, liquid paraffin, talc, isomerized sugar, sodium metabisulfite, methylparaben, propylparaben, magnesium stearate, milk sugar, normal saline, flavorings and colorants.

The composition according to the present invention may be used as drugs, food additives, or food. When the composition is used as drugs, the composition may be administered in oral or parenteral pathway. The formulation type of the composition may vary depending on its usage. For example, the composition may be formulated in the form of plasters, granules, lotions, powders, syrups, liquids, solutions, aerosols, ointments, fluid extracts, emulsions, suspensions, infusions, tablets, injections, capsules, pills, and the like.

The present invention is further explained in more detail with reference to the following examples. These examples, however, should not be interpreted as limiting the scope of the present invention in any manner.

Example Example 1 Synthesis of the Compound of Chemical Formula 2

The compound of following Chemical Formula 2 was synthesized:

The synthesized compounds were summarized in following Table 1. In the table, hydrogen atom used as R and/or R′ was not marked.

TABLE 1 Compound No. CODE n R and R′ 1 KHG23168 0 2-F, 5-NO₂ 2 KHG23169 0 2-Cl, 4-F 3 KHG23170 0 3-Cl, 4-Me 4 KHG23171 0 4-F 5 KHG23172 0 2-F, 5-Cl 6 KHG23173 0 2-F, 4-Cl 7 KHG23174 0 2-Cl, 4-Me 8 KHG23175 0 4-Me 9 KHG23176 0 4-CN 10 KHG23177 0 11 KHG23178 0 4-Br 12 KHG23179 0 3-F, 4-OMe 13 KHG23184 0 4-Cl 14 KHG23185 0 3-Cl, 5-Cl 15 KHG23185 0 3,-Cl, 5-Cl 16 KHG23186 0 4-Et 17 KHG23187 1 4-Me 18 KHG23188 2 4-Me 19 KHG23189 1 3-F, 4-F 20 KHG23190 2 4-F 21 KHG23191 0 2-Br, 4-Me 22 KHG23192 0 4-OEt 23 KHG23379 0 4-iPr 24 KHG23380 0 4-NO₂ 25 KHG23381 0 4-Decyl 26 KHG23382 0 3-CO₂Et 27 KHG23383 0 4-nHexyl 28 KHG23384 0 4-n-BuO 29 KHG23385 0 4-CO₂Et 30 KHG23386 0 4-n-Heptyl 31 KHG23387 0 4-CH₂CN 32 KHG23388 0 4-n-Bu 33 KHG23389 0 4-OPh 34 KHG23391 0 2-Cl, 6-Cl, 4-CF₃ 35 KHG23392 0 2-F, 3-F, 4-F 36 KHG23393 0 2-Me, 4-OMe 37 KHG23394 0 3-CF₃, 5-CF₃ 38 KHG23395 0 2-Cl, 3-Cl, 5-Cl, 6-Cl, 39 KHG23397 0 3-Cl, 4-Me 40 KHG23398 0 2-Cl, 6-Cl, 4-CF₃O 41 KHG23399 0 3-F, 4-MeO

Synthesis of Compound KHG23168 [2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2-fluoro-5-nitrophenyl)acetamide hydrochloride] [n=0, (R, R′; containing benzyl group, identical thereafter)=C₆H₃(2-F, 5-NO₂)]

The compound was synthesized by conducting the reaction of following Reaction Formula 1:

0.549 g of Compound I [4-chloro-N-(2-fluoro-5-nitrophenyl)-3-oxobutyramide, 0.002 mol] was dissolved in 5 mL of ethanol. Then, 0.236 g of Compound II (guanylthiourea, 0.002 mol) was added hereto, and heated to reflux for 2 hours. The obtained reaction mixture was cooled to room temperature, and then the suitable amount of ethylether was added to crystallize, generating precipitation within 12 hours. The precipitation was filtrated to obtain white crystalline solid III (0.648 g).

yield: 86%, melting point: 248.4-250.1° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.88 (s, 2H, 4-CH₂), 7.16 (s, 1H, vinyl-H), 7.58 (app. t, 1H, J=9.5 Hz, ArH), 8.05 (ddd, 1H, J=9.1 Hz, ArH), 8.28 (br. s, 3H, NH), 8.95 (dd, 1H, J=6.7, 2.9 Hz, ArH), 10.45 (s, 1H, amide NH), 12.23 (br. s, 1H, NH).

Hereinafter, following compounds were synthesized by the same method as above, except that the starting materials were suitably selected according to the final products.

KHG23169 N-(2-chloro-4-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(2-Cl, 4-F)]

yield: 70%, melting point: 232.8-233.9° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.78 (s, 2H, 4-CH₂), 7.15 (s, 1H, vinyl-H), 7.22 (td, 1H, J=8.5, 2.9 Hz, ArH), 7.51 (dd, 1H, J=8.6, 2.9 Hz, ArH), 7.65 (dd, 1H, J=8.9, 5.9 Hz, ArH), 8.32 (br. s, 3H, NH), 9.82 (s, 1H, amide, NH), 12.33 (br. s, 1H, NH).

KHG23170 N-(3-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(3-Cl, 4-CH₃)]

yield: 63%, melting point: 238.6-240.4° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.26 (s, 3H, 4-CH₃), 3.72 (s, 2H, 4-CH₂), 7.13 (s, 1H, vinyl-H), 7.26 (d, 2H, J=8.4 Hz, ArH), 7.38 (dd, 2H, J=8.3, 2.0 Hz, ArH), 7.80 (d, 1H, J=1.9 Hz, ArH), 8.30 (br. s, 3H, NH), 10.43 (s, 1H, amide, NH), 12.30 (br. s, 1H, NH).

KHG23171 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-fluorophenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-F)]

yield: 58%, melting point: 207.3-208.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.72 (s, 2H, 4-CH₂), 7.12-7.18 (m, 3H, vinyl-H and ArH), 7.60-7.65 (m, 2H, ArH), 8.30 (br. s, 3H, NH), 10.35 (s, 1H, amide, NH), 12.25 (br. s, 1H, NH).

KHG23172 N-(5-chloro-2-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(2-F, 5-Cl)]

yield: 66%, melting point: 209.3-210.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.77 (s, 2H, 4-CH₂), 6.94 (s, 1H, vinyl-H), 6.94 (ddd, 1H, J=8.8, 4.2, 2.8 Hz, ArH), 7.33 (dd, 1H, J=10.5, 8.9 Hz, ArH), 7.86 (br. s, 3H, NH), 8.05 (dd, 1H, J=6.7, 2.6 Hz, ArH), 10.14 (s, 1H, amide, NH), 12.28 (br. s, 1H, NH).

KHG23173 N-(4-chloro-2-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(2-F, 4-Cl)]

yield: 68%, melting point: 237.2-239.8° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.80 (s, 2H, 4-CH₂), 7.13 (s, 1H, vinyl-H), 7.24-7.27 (m, 1H, ArH), 7.50 (dd, 1H, J=10.7, 2.3 Hz, ArH), 7.86-7.93 (m, 1H, ArH), 8.31 (br. s, 3H, NH), 10.10 (s, 1H, amide, NH), 12.35 (br. s, 1H, NH).

KHG23174 N-(2-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(2-Cl, 4-CH₃)]

yield: 66%, melting point: 218.6-220.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.27 (s, 3H, 4-CH₃), 3.77 (s, 2H, 4-CH₂), 7.11-7.55 (m, 4H, vinyl-H and ArH), 8.32 (br. s, 3H, NH), 9.66 (s, 1H, amide, NH), 12.33 (br. s, 1H, NH).

KHG23175 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-p-tolylacetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-CH₃)]

yield: 68%, melting point: 236.2-238.3

¹H NMR (300 MHz, DMSO-d₆) δ 2.23 (s, 3H, 4-CH₃), 3.69 (s, 2H, 4-CH₂), 7.08-7.49 (m, 5H, vinyl-H and ArH), 8.29 (br. s, 3H, NH), 10.18 (s, 1H, amide, NH), 12.32 (br. s, 1H, NH).

KHG23176 N-(4-cyanophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-CN)]

yield: 78%, melting point: 218.4-219.4° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.80 (s, 2H, 4-CH₂), 7.16 (s, 1H, vinyl-H), 7.78 and 7.82 (AB pattern, 4H, J_(AB)=8.6 Hz, ArH), 8.31 (br. s, 3H, NH), 10.88 (s, 1H, amide, NH), 12.39 (br. s, 1H, NH).

KHG23177 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-phenylacetamide hydrochloride [n=0, (R, R′)=C₆H₅]

yield: 62%, melting point: 197.8-198.1° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.72 (s, 2H, 4-CH₂), 7.04 (app. t, 1H, J=74 Hz, ArH), 7.12 (s, 1H, vinyl-H), 7.29 (app. t, 2H, J=7.9 Hz, ArH), 7.60 (d, 2H, H=7.7 Hz, ArH), 8.30 (br. s, 3H, NH), 10.27 (s, 1H, amide, NH), 12.30 (br. s, 1H, NH).

KHG23178 N-(4-bromophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-Br)]

yield: 79%, melting point: 246.4-247.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.73 (s, 2H, 4-CH₂), 7.12 (s, 1H, vinyl-H), 7.47-7.60 (m, 4H, ArH), 8.27 (br. s, 3H, NH), 10.44 (s, 1H, amide, NH), 12.26 (br. s, 1H, NH).

KHG23179 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3-fluoro-4-methoxyphenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(3-F, 4-OCH₃)]

yield: 47%, melting point: 225.8-228.4° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.69 (s, 2H, 4-CH₂), 3.79 (s, 3H, 4-OCH₃), 7.07-7.61 (m, 4H, vinyl-H and ArH), 8.29 (br. s, 3H, NH), 10.38 (s, 1H, amide, NH), 12.38 (br. s, 1H, NH).

KHG23184 N-(4-chlorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-Cl)]

yield: 68%, melting point: 244.3-245.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.73 (s, 2H, 4-CH₂), 7.14 (s, 1H, vinyl-H), 7.36 (d, 2H, J=8.8 Hz, ArH), 7.64 (d, 2H, J=8.8 Hz, ArH), 8.28 (br. s, 3H, NH), 10.42 (s, 1H, amide, NH), 12.20 (br. s, 1H, NH).

KHG23185 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3,5-dichlorophenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(3-Cl, 5-Cl)]

yield: 91%, melting point: 248.5-249.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.77 (s, 2H, 4-CH₂), 7.16 (s, 1H, vinyl-H), 7.28 (t, 1H, J=1.8 Hz, ArH), 7.72 (d, 2H, J=1.8 Hz, ArH), 8.29 (br. s, 3H, NH), 10.84 (s, 1H, amide, NH), 12.35 (br. s, 1H, NH).

KHG23186 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-ethylphenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-CH₂CH₃)]

yield: 38%, melting point: 228.0-229.1° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.15 (t, 3H, J=7.6 Hz, 4-CH₂CH₃), 2.54 (q, 2H, H=7.6 Hz, 4-CH₂CH₃), 3.70 (s, 2H, 4-CH₂), 7.12 (s, 1H, vinyl-H), 7.13 (d, 2H, J=8.3 Hz, ArH), 7.50 (d, 2H, J=8.4 Hz, ArH), 8.29 (br. s, 3H, NH), 10.17 (s, 1H, amide, NH), 12.23 (br. s, 1H, NH).

KHG23187 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methylbenzyl)acetamide hydrochloride [n=1, (R, R′)=C₆H₄(4-CH₃)]

yield: 44%, melting point: 187.9-188.6° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.27 (s, 3H, 4-CH₃), 3.54 (s, 2H, 4-CH₂), 4.23 (d, 2H, J=5.8 Hz, NHCH₂), 7.06 (s, 1H, vinyl-H), 7.12 (s, 4H, ArH), 8.31 (br. s, 3H, NH), 8.54 (t, 1H, J=5.8 Hz, NHCH₂), 12.35 (br. s, 1H, NH).

KHG23188 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methylphenethyl)acetamide hydrochloride [n=2, (R, R′)=C₆H₄(4-CH₃)]

yield: 17%, melting point: 169.3-170.1° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.26 (s, 3H, 4-CH₃), 2.65 (t, 2H, J=6.9 Hz, —NHCH₂CH ₂-), 3.24 (app. q, 2H, J=6.7 Hz, —NHCH ₂CH₂—), 3.40 (s, 2H, 4-CH₂), 6.81 (s, 1H, vinyl-H), 7.03-7.09 (m, 4H, ArH), 7.90 (br. s, 4H, NH), 8.04 (br. t, 1H, J=5.5 Hz, —NHCH₂CH₂—), 12.25 (br. s, 1H, NH)

KHG23189 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3,4-difluorobenzyl)acetamide hydrochloride [n=1, (R, R′)=C₆H₃(3-F,4-F)]

yield: 89%, melting point: 206.9-207.6° C.

¹H NMR (300 MHz, DMSO-d₆) δ 3.56 (s, 2H, 4-CH₂), 4.27 (d, 2H, J=6.0 Hz, NHCH₂), 7.08-7.42 (m, 4H, vinyl-H and ArH), 8.30 (br. s, 3H, NH), 8.67 (t, 1H, J=6.0 Hz, NHCH₂), 12.39 (br. s, 1H, NH).

KHG23190 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-fluorophenethyl)acetamide hydrochloride [n=2, (R, R′)=C₆H₄(4-F)]

yield: 91%, melting point:

¹H NMR (300 MHz, DMSO-d₆) δ 2.69 (app. t, 2H, J=7.2 Hz, NHCH₂CH₂), 3.27 (app. q, 2H, J=6.5 Hz, NHCH₂CH₂), 3.44 (s, 2H, 4-CH₂), 6.96 (s, 1H, vinyl-H), 7.05-7.23 (m, 4H, ArH), 8.13 (t, 1H, J=5.4 Hz, NHCH₂CH₂), 8.25 (br. s, 3H, NH), 12.39 (br. s, 1H, NH).

KHG23191 N-(2-bromo-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(2-Br, 4-CH₃)]

yield: 47%, melting point: 219.7-220.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 2.28 (s, 3H, 4-CH₃), 3.76 (s, 2H, 4-CH₂), 7.15-7.48 (m, 4H, vinyl-H and ArH), 8.34 (br. s, 3H, NH), 9.57 (s, 1H, amide NH), 12.47 (br. s, 1H, NH).

KHG23192 N-(4-ethoxyphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-OCH₂CH₃)]

yield: 78%, melting point: 242.1-242.6° C.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (t, 3H, J=6.9 Hz, 4-OCH₂CH₃), 3.68 (s, 2H, 4-CH₂), 3.97 (q, 2H, J=6.9 Hz, 4-OCH₂CH₃), 6.84-6.87 (m, 2H, ArH), 7.10 (s, 1H, vinyl-H), 7.47-7.50 (m, 2H, ArH), 8.29 (br. s, 3H, NH), 10.09 (s, 1H, amide NH), 12.34 (br. s, 1H, NH).

KHG23379 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-isopropylphenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H_(4{)4-CH(CH₃)₂}]

yield: 42%, melting point: 220.0˜223.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.21 (s, 1H, amide NH), 8.31 (br. s, 4H, NH), 7.51 (d, 2H, J=8.6 Hz, Ar—H), 7.16 (d, 2H, J=8.5 Hz, Ar—H), 7.11 (s, 1H, vinyl-H), 3.70 (s, 2H, CH2), 2.78 (m, 1H, J=6.8 Hz, CH(CH3)2), 1.18, 1.16 (2s, 6H, 2×CH3).

KHG23380 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-nitrophenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-NO₂)]

yield: 86%, melting point: 245.3˜245.9° C.

¹H NMR (300 MHz, DMSO-d₆) δ 11.04 (s, 1H, amide NH), 8.28 (br. s, 4H, NH), 8.21 (d, 2H, J=9.2 Hz, Ar—H), 7.88 (d, 2H, J=9.2 Hz, Ar—H), 7.16 (s, 1H, vinyl-H), 3.83 (s, 2H, CH₂).

KHG23381 N-(4-decylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H_(4{)4-(CH₂)₉CH₃}]

yield: 62%, melting point: 240.0˜242.9° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.19 (s, 1H, amide NH), 8.31 (br. s, 4H, NH), 7.08˜7.50 (m, 4H, Ar—H), 7.11 (s, 1H, vinyl-H), 3.70 (s, 2H, CH₂), 2.50 (m, 2H, —CH₂—), 1.51 (m, 2-H, —CH₂—), 1.23 (m, 14H, (CH₂)₇), 0.84 (t, 3H, J=6.6 Hz, CH₃).

KHG23382 ethyl 3-(2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamido)benzoate hydrochloride [n=0, (R, R′)=C₆H₄(3-COOCH₂CH₃)]

yield: 58%, melting point: 208.3˜209.3° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.57 (s, 1H, amide NH), 8.30 (br. s, 4H, NH), 8.28 (m, 1H, Ar—H), 7.87 (d, 1H, J=8.1 Hz, Ar—H), 7.64 (app. d, 1H, J=7.7 Hz, Ar—H), 7.45 (t, 1H, J=7.9 Hz, Ar—H), 7.13 (s, 1H, vinyl-H), 4.31 (q, 2H, OCH₂CH₃), 3.76 (s, 2H, CH₂), 1.32 (t, 3H, OCH₂CH₃).

KHG23383 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-hexylphenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H_(4{)4-(CH₂)₅CH₃}]

yield: 65%, melting point: 245.4˜246.4° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.14 (s, 1H, amide NH), 8.28 (br. s, 4H, NH), 7.48 (d, 2H, J=8.3 Hz, Ar—H), 7.11 (s, 1H, vinyl-H), 7.10 (d, 2H, J=8.3 Hz, Ar—H), 3.69 (s, 2H, CH₂), 2.50 (m, 2H, —CH₂—), 1.52 (m, 2-H, —CH₂—), 1.25 (m, 6H, (CH₂)₃), 0.84 (m, 3H, CH₃).

KHG23384 N-(4-butoxyphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H_(4{)4-O(CH₂)₃CH₃}]

yield: 66%, melting point: 243.2˜244.3° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.13 (s, 1H, amide NH), 8.31 (br. s, 4H, NH), 7.49 (d, 1H, J=9.0 Hz, Ar—H), 7.09 (s, 1H, vinyl-H), 6.85 (d, 2H, J=8.9 Hz, Ar—H), 3.90 (t, 2H, J=6.4 Hz, OCH₂CH₂CH₂CH₃), 3.68 (s, 2H, CH₂), 1.66 (m, 2H, OCH₂CH₂CH₂CH₃), 1.41 (m, 2H, J=7.5 Hz, OCH₂CH₂CH₂CH₃), 0.91 (t, 3H, CH₃).

KHG23385 ethyl 4-(2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamido)benzoate hydrochloride [n=0, (R, R′)=C₆H₄(4-COOCH₂CH₃)]

yield: 62%, melting point: 219.5˜220.5° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.73 (s, 1H, amide NH), 8.32 (br. s, 4H, NH), 7.91 (d, 2H, J=8.8 Hz, Ar—H), 7.76 (d, 2H, J=8.8 Hz, Ar—H), 7.15 (s, 1H, vinyl-H), 4.28 (q, 2H, J=7.0 Hz, OCH₂CH₃), 3.79 (s, 2H, CH₂), 1.30 (t, 3H, J=7.1 Hz, OCH₂CH₃).

KHG23386 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-hexylphenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-(CH₂)₂CH₃)]

yield: 73%, melting point: 246.6˜247.1° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.17 (s, 1H, amide NH), 8.30 (br. s, 4H, NH), 7.48 (d, 2H, J=8.2 Hz, Ar—H), 7.11 (s, 1H, vinyl-H), 7.09 (d, 2H, J=8.4 Hz, Ar—H), 3.69 (s, 2H, CH₂), 2.52˜2.43 (m, 2H, —CH₂—), 1.52 (quin, 2-H, J=6.8 Hz, —CH₂—), 1.24 (br. d, 8H, (CH₂)₄), 0.84 (m, 3H, J=6.7 Hz, CH₃).

KHG23387 N-(4-(cyanomethyl)phenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₄(4-CH₂CN)]

yield: 81%, melting point: 237.1˜238.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H, amide NH), 8.30 (br. s, 4H, NH), 7.63 (d, 2H, J=8.6 Hz, Ar—H), 7.19 (d, 2H, J=8.6 Hz, Ar—H), 7.12 (s, 1H, vinyl-H), 3.93 (s, 2H, CH2), 3.73 (s, 2H, CH₂).

KHG23388 N-(4-butylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H_(4{)4-(CH₂)₃CH₃}]

yield: 70%, melting point: 243.9˜244.7° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.19 (s, 1H, amide NH), 8.31 (br. s, 4H, NH), 7.49 (d, 2H, J=8.3 Hz, Ar—H), 7.11 (s, 1H, vinyl-H), 7.10 (d, 2H, J=7.2 Hz, Ar—H), 3.70 (s, 2H, CH₂), 2.53˜2.49 (m, 2H, —CH₂—), 1.52 (m, 2-H, J=7.4 Hz, —CH₂—), 1.28 (m, 2H, J=7.3 Hz, —CH₂—), 0.88 (m, 3H, J=7.29 Hz, CH₃).

KHG23389 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-phenoxyphenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H_(4{)4-O(C₆H₅)}]

yield: 62%, melting point: 236.2˜236.8° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.28 (s, 1H, amide NH), 8.28 (br. s, 4H, NH), 7.63˜6.93 (m, 10H, Ar—H, vinyl-H), 3.71 (s, 2H, CH₂).

KHG23391 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,6-dichloro-4-(trifluoromethyl)phenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₂(2-Cl,6-Cl,4-CF₃)]

yield: 71%, melting point: 293.8˜302.3° C. (decomposition)

¹H NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H, amide NH), 8.36 (br. s, 4H, NH), 7.98 (m, 2H, Ar—H), 7.17 (s, 1H, vinyl-H), 3.80 (s, 2H, CH₂).

KHG23392 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,3,4-trifluorophenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₂(2-F, 3-F, 4-F)]

yield: 39%, melting point: 229.0˜229.9° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (s, 1H, amide NH), 8.33 (br. s, 4H, NH), 7.61˜7.24 (m, 2H, Ar—H), 7.13 (s, 1H, vinyl-H), 3.80 (s, 2H, CH₂).

KHG23393 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methoxy-2-methylphenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(2-Me,4-OMe)]

yield: 64%, melting point: 228.7˜229.2° C.

¹H NMR (300 MHz, DMSO-d₆) δ 9.42 (s, 1H, amide NH), 8.30 (br. s, 4H, NH), 7.76 (m, 2H, J=8.5 Hz, Ar—H), 6.77 (s, 1H, vinyl-H), 6.72 (m, 1H, J=8.3 Hz, Ar—H), 3.71 (s, 3H, OCH₃), 3.68 (s, 2H, CH₂), 2.11 (s, 3H, CH₃).

KHG23394 N-(3,5-bis(trifluoromethyl)phenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)═C₆H_(3{)3,5-(CF₃)₂}]

yield: 77%, melting point: 186.6˜187.6° C.

¹H NMR (300 MHz, DMSO-d₆) δ 11.17 (br. s, 1H, amide NH), 8.33 (s, 2H, Ar—H), 8.25 (br. s, 4H, NH), 7.76 (s, 1H, Ar—H), 7.17 (s, 1H, vinyl-H), 3.82 (s, 2H, CH₂).

KHG23395 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,3,5,6-tetrachlorophenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₁(2-Cl, 3-Cl, 5-Cl, 6-Cl)]

yield: 74%, melting point: 293.8˜302.3° C. (decomposition)

¹H NMR (300 MHz, DMSO-d₆) δ 1041 (s, 1H, amide NH), 8.30 (br. s, 4H, NH), 8.11 (s, 1H, Ar—H), 7.16 (s, 1H, vinyl-H), 3.79 (s, 2H, CH₂).

KHG23397 N-(3-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(3-Cl,4-Me)]

yield: 67%, melting point: 247.4˜247.9° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.49 (s, 1H, amide NH), 8.31 (br. s, 4H, NH), 7.81 (d, 1H, J=2.0 Hz, Ar—H), 7.41 (dd, 1H, J=8.2, 2.1 Hz, Ar—H), 7.26 (d, 1H, J=8.2 Hz, Ar—H), 7.13 (s, 1H, vinyl-H), 3.73 (s, 3H, OCH₃), 2.26 (s, 3H, OCH₃).

KHG23398 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,6-dichloro-4-(trifluoromethoxy)phenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₂(2,6-Cl₂,4-OCF₃)]

yield: 74%, melting point: 293.8˜302.3° C. (decomposition)

¹H NMR (300 MHz, DMSO-d₆) δ 1041 (s, 1H, amide NH), 8.30 (br. s, 4H, NH), 8.11 (s, 1H, Ar—H), 7.16 (s, 1H, vinyl-H), 3.79 (s, 2H, CH₂).

KHG23399 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3-fluoro-4-methoxyphenyl)acetamide hydrochloride [n=0, (R, R′)=C₆H₃(3-F,4-OMe)]

yield: 58%, melting point: 235.7˜237.0° C.

¹H NMR (300 MHz, DMSO-d₆) δ 9.82 (s, 1H, amide NH), 8.33 (br. s, 4H, NH), 7.65 (t, 1H, J=8.2 Hz, Ar—H), 7.10 (d, 1H, J=6.4 Hz, Ar—H), 7.05 (s, 1H, vinyl-H), 6.95 (d, 1H, J=8.0 Hz, Ar—H), 3.76 (s, 3H, OCH₃), 2.27 (s, 3H, OCH₃).

Example 2 Synthesis of the Compound of Chemical Formula 3

The compound of following Chemical Formula 3 was synthesized:

The synthesized compounds were summarized in following Table 2. In the table, hydrogen atom used as R and/or R′ was not marked.

TABLE 2 CODE R and R′ HX 1 KHG24022 3-[O(CO)NH]-4 HCl 2 KHG24024 4-Cl HCl 3 KHG24025 4-F HCl 4 KHG24026 2-F, 4-F HCl 5 KHG24037 3-[OCH₂C(O)NH]-4 HCl 6 KHG24038 4-Ph HCl 7 KHG24039 3-(CHCHCHCH)-4 HCl 8 KHG24040 4-Me HBr 9 KHG24041 4-OMe HBr 10 KHG24373 2-Cl HBr 11 KHG24374 2-MeO HBr 12 KHG24375 4-NO₂ HBr 13 KHG24376 2-OMe, 4-OMe HBr 14 KHG24377 2-F, 4-MeO HBr 15 KHG24379 2-Cl, 4-Cl HBr 16 KHG24380 HBr 17 KHG24381 4-Br HBr 18 KHG24382 3-Me HBr 19 KHG24383 3-F HBr 20 KHG24384 2-F HBr 23 KHG24385 3-CF₃ HBr 24 KHG24386 3-Br HBr 25 KHG24387 4-Et HBr 26 KHG24388 3-Cl HBr 27 KHG24389 3-NO₂ HBr 28 KHG24390 3-Cl, 4-Cl HBr 28 KHG24391 2-F, 5-F HBr 30 KHG24392 3-CF₃, 5-CF₃ HBr

KHG24022 2-(4-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-yl)thiazole-2-yl)guanidine hydrochloride [(R, R′)=3-[O(CO)NH]-4, HX=HCl]

The compound was synthesized by conducting the reaction of following Reaction Formula 2:

Guanylthiourea IV (1.69 mmol) and 5-chloroacetyl-2-benzoxazolinone V (1.69 mmol) were heated to reflux for 4 hours under ethanol solvent. Then, the reaction mixture was left at room temperature for 1 hour to generate solid. The obtained solid was filtrated to obtain thiazole-based compound VI.

yield: 74%, melting point: 313.7° C.

1H NMR (400 MHz, DMSO-d6) δ 11.78 (br. s, 1H, benzoxazol NH), 8.20 (br. s, 4H, NH), 7.92 (d, 1H, J=1.2 Hz, Ar—H), 7.75 (dd, 1H, J=8.2, 1.5 Hz, Ar—H), 7.11 (d, 1H, J=8.2 Hz, Ar—H).

Hereinafter, following compounds were synthesized by the same method as above, except that the starting materials were suitably selected according to the final products.

KHG24023 2-(5-(4-fluorobenzyl)-4-methylthiazole-2-yl)guanidine hydrochloride [(R, R′)=4-F, HX=HCl]

yield: 66%, melting point: 245.6° C.

1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H, amide NH), 8.34 (br. s, 4H, NH), 7.68˜7.64 (m, 2H, Ar—H), 7.20˜7.64 (t, 2H, Ar—H), 2.49 (s, 3H, CH₃).

KHG24024 2-(4-(4-chlorophenyl)thiazole-2-yl)guanidine hydrochloride [(R, R′)=4-Cl, HX=HCl]

yield: 75%, melting point: 264.9° C.

1H NMR (400 MHz, DMSO-d6) δ 8.33 (br. s, 4H, NH), 8.00 (d, 2H, J=8.5 Hz, Ar—H), 7.82 (s, 1H, Vinyl-H), 7.48 (d, 2H, J=8.5 Hz, Ar—H).

KHG24025 2-(4-(4-fluorophenyl)thiazole-2-yl)guanidine hydrochloride [(R, R′)=4-F, HX=HCl]

yield: 69%, melting point: 223.3° C.

1H NMR (400 MHz, DMSO-d6) δ 8.32 (br. s, 4H, NH), 8.03˜7.97 (m, 2H, Ar—H), 7.74 (s, 1H, Vinyl-H), 7.28˜7.22 (m, 2H, Ar—H).

KHG24026 2-(4-(2,4-difluorophenyl)thiazole-2-yl)guanidine hydrochloride [(R, R′)=2-F, 4-F, HX=HCl]

yield: 66%, melting point: 248.9° C.

1H NMR (400 MHz, DMSO-d6) δ 8.35 (br. s, 4H, NH), 8.24˜8.16 (m, 2H, Ar—H), 7.60 (s, 1H, Vinyl-H), 7.42˜7.13 (m, 2H, Ar—H), 7.19˜7.13 (m, 1H, Ar—H).

KHG24037 2-(4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)thiazole-2-yl)guanidine hydrochloride [(R, R′)=3-[OCH₂C(O)NH]-4, HX=HCl]

yield: 91%, melting point: 233.3° C.

1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H, benzoxazin NH) 8.36 (br. s, 4H, NH), 7.52˜6.97 (m, 5H, Ar—H), 4.60 (s, 1H, Vinyl-H).

KHG24038 2-(4-(biphenyl-4-yl)thiazole-2-yl)guanidine hydrochloride [(R, R′)=4-Ph, HX=HCl]

yield: 91%, melting point: 300.3° C.

1H NMR (400 MHz, DMSO-d6) δ 8.23 (br. s, 4H, NH), 8.05˜8.03 (m, 2H, Ar—H), 7.85 (s, 1H, Vinyl-H), 7.76˜7.71 (m, 4H, Ar—H), 7.51˜7.37 (m, 3H, Ar—H).

KHG24039 2-(4-(naphthalene-2-yl)thiazole-2-yl)guanidine hydrochloride [(R, R′)=3-(CHCHCHCH)-4, HX=HCl]

yield: 91%, melting point: 263.2° C.

1H NMR (400 MHz, DMSO-d6) δ 8.54˜8.53 (m, 1H, Ar—H), 8.28 (br. s, 4H, NH), 8.06˜7.93 (m, 4H, Ar—H), 7.92 (s, 1H, Vinyl-H), 7.54˜7.49 (m, 3H, Ar—H).

KHG24040 2-(4-p-tolylthiazole-2-yl)guanidine hydrobromide [(R, R′)=4-CH3, HX=HBr]

yield: 86.6%, melting point: 281˜284° C.

1H NMR (300 MHz, DMSO-d6) δ 8.17 (br-s, 4H, guanyl-NH), 7.86 (d, 2H, J=8.7 Hz, Ar—H), 7.6 (s, 1H, vinyl-H)), 6.99 (d, 2H, J=8.8 Hz, Ar—H), 3.79 (s, 3H, CH₃)

KHG24041 2-(4-(4-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=4-OCH3, HX=HBr]

yield: 83.6%, melting point: 225˜227° C.

1H NMR (300 MHz, DMSO-d6) δ 8.18 (br-s, 4H, guanyl-NH), 7.82 (d, 2H, J=8.0 Hz, Ar—H), 7.7 (s, 1H, vinyl-H)), 7.24 (d, 2H, J=8.0 Hz, Ar—H), 2.33 (s, 3H, CH₃)

KHG 24373 2-(4-(2-chlorophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=2-Cl, HX=HBr]

yield: 70.4%, melting point: 211.9° C.

1H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H, HBr) 8.23 (s, 4H, (NH₂)₂) 7.87˜7.84 (m, 1H, J=2.3 Hz, Ar—H) 7.76 (s, 1H, Vinyl-H) 7.60˜7.57 (m, 1H, J=2.3 Hz, Ar—H) 7.48˜7.42 (m, 2H, J=3.7 Hz, Ar—H).

KHG 24374 2-(4-(2-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=2-OCH₃, HX=HBr]

yield: 89.3% melting point: 245.4° C.

1H NMR (300 MHz, DMSO-d6) δ 8.17 (s, 4H, (NH₂)₂) 8.01 (d, 1H, J=6.6 Hz, Ar—H) 7.78 (s, 1H, Vinyl-H) 7.36 (t, 1H, J=6.6 Hz, Ar—H) 7.15 (d, 1H, J=7.8 Hz, Ar—H)

7.04 (t, 1H, J=7.1 Hz, Ar—H) 3.92 (s, 3H, OCH3).

KHG 24375 2-(4-(4-nitrophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=4-NO₂, HX=HBr]

yield: 98%, melting point: 250.8° C.

1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, 4H, J=3.7 Hz, Ar—H) 8.20 (s, 4H, (NH₂)₂) 8.14 (s, 1H, Vinyl-H).

KHG 24376 2-(4-(2,4-dimethoxyphenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=2-OCH₃, 4-OCH₃, HX=HBr]

yield: 81.3%, melting point: 213.0° C.

1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, 1H, HBr) 8.17 (s, 4H, (NH₂)₂) 7.93 (d, 1H, J=8.6 Hz, Ar—H) 7.59 (s, 1H, Vinyl-H) 6.69 (s, 1H, Ar—H) 6.59 (d, 1H, J=8.6 Hz, Ar—H) 3.91 (s, 3H, OCH3) Hz, Ar—H) 3.81 (s, 3H, OCH3).

KHG 24377 2-(4-(2-fluoro-4-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=2-F, 4-OCH₃, HX=HBr]

yield: 36.8%, melting point: 202.6° C.

1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 4H, (NH₂)₂) 8.00 (t, 1H, J=9.0 Hz, Ar—H) 7.50 (s, 1H, Vinyl-H) 6.96 (d, 1H, J=11.3 Hz, Ar—H) 6.86 (d, 1H, J=6.3 Hz, Ar—H) 3.82 (s, 3H, OCH3).

HG 24379 2-(4-(2,4-dichlorophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=2-Cl, 4-Cl, HX=HBr]

yield: 74.5%, melting point: 173.0° C.

1H NMR (300 MHz, DMSO-d6) δ 12.71 (s, 1H, HBr) 8.34 (s, 4H, (NH₂)₂) 7.92 (d, 1H, J=8.8 Hz, Ar—H) 7.80 (s, 1H, Vinyl-H) 7.74 (s, 1H, Ar—H) 7.50 (d, 1H, J=8.5 Hz, Ar—H).

KHG 24380 2-(4-phenylthiazole-2-yl)guanidine hydrobromide [(R, R′)=H, HX=HBr]

yield: 79%, melting point: 209.5° C.

¹H NMR (300 MHz, DMSO-d6) δ 11.96 (s, 1H, HBr) 8.22 (s, 4H, (NH₂)₂) 7.93 (d, 2H, J=7.1 Hz, Ar—H) 7.79 (s, 1H, Vinyl-H) 7.44 (t, 2H, J=7.3 Hz, Ar—H) 7.35 (t, 1H, J=7.3 Hz, Ar—H).

KHG 24381 2-(4-(4-bromophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=4-Br, HX=HBr]

yield: 40%, melting point: 278.5° C.

1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H, HBr) 8.20 (s, 4H, (NH₂)₂) 7.92 (d, 2H, J=8.6 Hz, Ar—H) 7.87 (s, 1H, Vinyl-H) 7.62 (d, 2H, J=8.6 Hz, Ar—H).

KHG 24382 2-(4-m-tolylthiazole-2-yl)guanidine hydrobromide [(R, R′)=3-CH₃, HX=HBr]

yield: 68%, melting point: 232.4° C.

1H NMR (300 MHz, DMSO-d6) δ 11.93 (s, 1H, HBr) 8.22 (s, 4H, (NH₂)₂) 7.75 (d, 2H, J=3.6 Hz, Ar—H) 7.71 (s, 1H, Vinyl-H) 7.33 (t, 1H, J=7.6 Hz, Ar—H) 7.17 (t, 1H, J=7.4 Hz, Ar—H) 2.36 (s, 3H, CH3).

KHG 24383 2-(4-(3-fluorophenyl)thiazole-2-yl)guanidine hydrobromide (R, R′)=3-F, HX=HBr]

yield: 63.1%, melting point: 242.1° C. 1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H, HBr) 8.17 (s, 4H, (NH₂)₂) 7.92 (s, 1H, Vinyl-H) 7.86˜7.80 (m, 2H, J=8.3 Hz, Ar—H) 7.50 (q, 1H, J=7.5 Hz, Ar—H) 7.20 (t, 1H, J=9.1 Hz, Ar—H).

KHG 24384 2-(4-(2-fluorophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=2-F, HX=HBr]

yield: 68.9%, melting point: 229.6° C.

1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H, HBr) 8.23 (s, 4H, (NH₂)₂) 8.10 (t, 2H, J=7.9 Hz, Ar—H) 7.67 (s, 1H, Vinyl-H) 7.44˜7.28 (m, 3H, Ar—H).

KHG 24385 2-(4-(3-(trifluoromethyl)phenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=3-CF₃, HX=HBr]

yield: 77.7%, melting point: 224.8° C.

1H NMR (300 MHz, DMSO-d6) δ 8.28 (m, 2H, J=6.1 Hz, Ar—H) 8.23 (s, 4H, (NH₂)₂) 8.07 (s, 1H, Vinyl-H) 7.70 (m, 2H, J=8.2 Hz, Ar—H).

KHG 24386 2-(4-(3-bromophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=3-Br, HX=HBr]

yield: 77.9%, melting point: 179.8° C.

1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 4H, (NH₂)₂) 8.16 (s, 1H, Ar—H) 7.99 (s, 1H, Vinyl-H) 7.95 (d, 1H, J=5.3 Hz, Ar—H) 7.57 (d, 1H, J=7.1 Hz, Ar—H) 7.40 (t, 1H, J=7.9 Hz, Ar—H).

KHG 24387 2-(4-(4-ethylphenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=4-C₂H₅, HX=HBr]

yield: 55.4%, melting point: 234.8° C.

1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H, HBr) 8.25 (s, 4H, (NH₂)₂) 7.83 (d, 2H, J=8.2 Hz, Ar—H) 7.71 (s, 1H, Vinyl-H) 7.26 (d, 2H, J=8.2 Hz, Ar—H) 2.63 (q, 2H, J=7.6 Hz, CH2CH3) 1.18 (t, 3H, J=8.2 Hz, Ar—H).

KHG 24388 2-(4-(3-chlorophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=3-Cl, HX=HBr]

yield: 63.6%, melting point: 210.4° C.

1H NMR (300 MHz, DMSO-d6) δ 8.21 (s, 4H, (NH₂)₂) 8.03 (s, 1H, Ar—H) 7.94 (s, 1H, Vinyl-H) 7.92 (m, 1H, Ar—H) 7.49˜7.39 (m, 2H, Ar—H).

KHG 24389 2-(4-(4-nitrophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=4-NO₂, HX=HBr]

yield: 89.5%, melting point: 237.8° C.

1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H, HBr) 8.69 (s, 1H, Ar—H) 8.43 (d, 2H, J=8.2 Hz, Ar—H) 8.22 (s, 4H, (NH₂)₂) 8.19 (m, 1H, Ar—H) 8.12 (s, 1H, Vinyl-H) 7.74 (t, 1H, J=8.0 Hz, Ar—H).

KHG 24390 2-(4-(3,4-dichlorophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=3-Cl, 4-Cl, HX=HBr]

yield: 66.2%, melting point: 256.3° C.

1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H, HBr) 8.25 (s, 1H, Ar—H) 8.17 (s, 4H, (NH₂)₂) 7.99 (s, 1H, Vinyl-H) 7.95 (d, 1H, J=6.4 Hz, Ar—H) 7.68 (d, 1H, J=8.5 Hz, Ar—H).

KHG 24391 2-(4-(2,5-difluorophenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=2-F, 5-F, HX=HBr]

yield: 79%, melting point: 252.1° C.

1H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H, HBr) 8.18 (s, 4H, (NH₂)₂) 8.00˜7.95 (m, 1H, Ar—H) 7.75 (s, 1H, Vinyl-H) 7.44˜7.35 (m, 1H, Ar—H) 7.30˜7.22 (m, 2H, Ar—H).

KHG 24392 2-(4-(3,5-bis(trifluoromethyl)phenyl)thiazole-2-yl)guanidine hydrobromide [(R, R′)=3-CF₃, 5-CF₃, HX=HBr]

yield: 27.6%, melting point: 265.6° C.

1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 2H, Ar—H) 8.32 (s, 1H, Ar—H) 8.21 (s, 4H, (NH₂)₂) 8.01 (s, 1H, Vinyl-H)

Experimental Example Assay for Inhibiting Activity Against T-Type Calcium Channel

In the present invention, in order to search an efficient inhibitor against T-type calcium channel, a primary assay for T-type calcium channel inhibiting activity was conducted by a high-efficient assay using FDSS6000, wherein mammal HEK293 cell lines (originated from human kidney carcinoma cells) which specifically expresses α1G of T-type calcium channel was used for primary assay. Through the primary assay, compounds which show meaningful inhibition effects were selected. The selected compounds were used in a second assay for T-type calcium channel inhibiting activity using electrophysiological whole cell patch clamp method, wherein mammal HEK293 cell lines (originated from human kidney carcinoma cells) which specifically expresses α_(1G) of T-type calcium channel was used for the second assay. As a reference drug, mibefradil which had been developed as T-type calcium channel inhibitor was used.

Experimental Example 1 Method of Assay for % Inhibiting Activity Against T-Type Calcium Channel Using FDSS6000

At 12-24 hours before being used for this assay, cells of HEK293 cell line (α_(1G) cell line: KCTC 10519BP, Korean Collection for Type Cultures), which stably express α_(1G) T-type calcium channel and Kir2.1, were sub-cultured in a poly-L-lysine treated 96-well plate with the density of 4×10⁴ per a well using a 96-well cell dispenser (Titertek). On the of assay, the 96-well plate to which the cells were attached were washed three times with HEPES buffer solution (150 mM of NaCl, 5 mM of KCl, 1 mM of MgCl₂, 2 mM of CaCl₂, 10 mM of HEPES, 10 mM of glucose; pH 7.4) using a 96-well plate automatic washing device (Bio Tek), then reacted with HEPES buffer solution containing 5 μM fluo-3/AM and 0.001% Pluronic F-127 under room temperature for 1 hour, to label with fluorescent dye, and then further washed two times with HEPES buffer solution.

Thereafter, at 10 minutes before the measurement using device FDSS6000, a washing with HEPES buffer solution containing 10 mM CaCl₂ was conducted once more, and the final volume was adjusted to 81 μl. Besides the above 96-well plate containing the cells, additional two drug 96-well plates were provided, wherein the 96-well plates contain inhibiting drug and KCl (final concentration: 75 mM) for activating T-type calcium channel, respectively. Since most of cell-based HTS devices are equipped with a liquid application system for injection of drug, but have no liquid sucking system, the inhibiting drug to be tested and KCl were respectively provided at the five-times higher concentration in 10 mM CaCl₂ HEPES buffer solution at the amount of 27 μl, diluted five-times at the final cell plate volume of 135 μl, and then used in this test. The concrete method of measurement using FDSS6000 was as follows: After recording the reference value of 20 seconds, the change of intracellular Ca²⁺ concentration which induced by treatment of the inhibiting drug to be tested for 75 seconds followed by administration of KCl was measured, wherein the percentage (%) inhibition effect of the test drug, through estimating the area of ratio value of 340/380 in the control without treatment of the test drug as 100%. As a reference drug, mibefradil was used.

For accurate calcium-imagination, the light source of 4 xenon lamps in FDSS6000 were radiated to make the cells exposed selectively to the excitation wavelength (340 nm and 380 nm) by computer-controlled filter wheel. Data was obtained at interval of each 1.23 second. The emitter fluorescence light inflowed through long-pass filter was obtained as an average 340/380 ratio value for each well in the 96-wells by using CCD camera and digital fluorescence analyzer in FDSS6000. All image data and analyses were obtained by using FDSS6000-exclusive program provide from Hamamatsu Photonics.

Experimental Example 2 Measurement of IC50 for T-Type Calcium Channel Activity in HEK293 Cells Using a Electrophysiological Method

10% Fetal bovine serum (FBS) and 1% penicillin/streptomycin (v/v) were added to Dulbecco's modified Eagle's medium (DMEM), to be used as a media solution. The cells were cultured in incubator under the wet condition of 95% air/5% CO₂ and temperature of 36.5° C. The media solution was refreshed every 3 or 4 days, and the cells were sub-cultured every week. Only the cells which express α_(1G) T-type calcium channel were cultured using G-418 (0.5 mg/ml) solution. The recording to the cells used in the T-type calcium channel activity analysis was conducted at 2-7 days after the cells were culturing on a cover slip coated with poly-L-lysine (0.5 mg/ml) when conducting every sub-culture. For analysis at a single cell level, the T-type calcium channel current was measured by an electrophysiological whole cell patch clamp method using EPC-9 amplifier (HEKA, German).

As solutions for analyzing T-type calcium channel activity, the solution comprising 140 mM of NaCl, 2 mM of CaCl₂, and 10 mM of HEPES (pH 7.4) was used as an extracellular solution, and the solution comprising 130 mM of KCl, 10 mM of HEPES, 11 mM of EGTA, and 5 mM of MgATP (pH 7.4) was used as an intracellular solution. The protocol for T-type calcium channel activity which is activated at low voltage is as follows: A micro glass electrode with the resistance of 3-4 MΩ wherein the above prepared intracellular solution is filled was pricked into a single cell, to make a whole-cell recording mode. Thereafter, the cell membrane potential was fixed to −100 mV, and then the inward current due to the T-type calcium channel activity when hypopolarizing to −30 mV (50 ms duration) was measured every 10 seconds. Each compound to be tested was dissolved in 100% dimethylsulfoxide (DMSO) to make a 10 mM stock solution. The effect of the compound on T-type calcium channel current compound was initially examined in the stock solution with the 1000-times diluted concentration of 10 μM (containing 0.1% DMSO) and then examined in the solution with the concentration for IC50 measurement (mostly 0.1 to 100 μM), to obtain IC₅₀ value. More specifically, the cells were treated each compound together with the extracellular solution for 30 to 60 seconds, and the inhibition level of peak current induced by the compound was calculated as percentage, to obtain the % inhibition value.

TABLE 3 % Inhibition [α1G, 10 μM) CODE using FDSS6000 1 KHG23168 21.63 2 KHG23169 23.19 3 KHG23170 30.68 4 KHG23171 21.52 5 KHG23172 27.58 6 KHG23173 28.06 7 KHG23174 18.82 8 KHG23175 23.80 9 KHG23176 20.52 10 KHG23177 23.31 11 KHG23178 34.47 12 KHG23179 30.76 13 KHG23184 24.87 14 KHG23186 29.78 15 KHG23187 21.39 16 KHG23188 19.34 17 KHG23189 19.29 18 KHG23190 20.96 19 KHG23191 18.00 20 KHG23192 16.84 21 KHG23737 16.07 23 KHG23393 3.8 24 KHG23380 11.4 25 KHG23185 12.3 26 KHG23383 5.7 27 KHG23389 25.40 28 KHG23396 3.0 29 KHG23391 0.8 30 KHG23386 4.5 31 KHG23390 11.6 32 KHG23394 41.5 33 KHG23392 22.7 34 KHG23381 6.2 35 KHG23384 6.1 36 KHG23399 3.4 37 KHG23395 2.7 38 KHG23379 14.7 39 KHG23385 5.9 40 KHG23397 14.2 41 KHG23398 0.2 42 KHG23387 3.2 43 KHG23382 24.0

[

 4] % Inhibition [α1G, 10 μM) KODE using FDSS6000 1 KHG24373 21.67 2 KHG24374 20.73 3 KHG24375 19.90 4 KHG24376 16.08 5 KHG24377 20.17 6 KHG24378 9.48 7 KHG24379 16.77 8 KHG24380 19.56 9 KHG24381 20.77 10 KHG24382 22.28 11 KHG24383 21.55 12 KHG24384 20.26 13 KHG24385 15.78 14 KHG24386 10.95 15 KHG24387 17.05 16 KHG24388 10.79 17 KHG24389 21.86 18 KHG24390 7.32 19 KHG24391 20.81 20 KHG24392 12.88 21 KHG24393 13.43 22 KHG24394 12.67 23 KHG24024 13.04 24 KHG24025 19.92 25 KHG24026 19.77 26 KHG24037 21.18 27 KHG24038 14.18 28 KHG24039 21.89 28 KHG24040 16.22 30 KHG24022 10.14 31 KHG24041 13.34

[

5] % Inhibition on HEK293 (100 mM) IC₅₀ on HEK293 Mibefradil 0.84

88.2 0.31 ± 0.22

87.8 0.78 ± 0.08

As shown in above Tables 3, 4, and 5, it is revealed that the thiazole-based compounds of the present invention have an excellent inhibiting activity against T-type calcium channel.

Due to such excellent T-type calcium channel inhibiting activity, the thiazole-based compounds of the present invention can be used in the treatment and/or prevention of nervous diseases, pain, epilepsy, hypertension, angina pectoris, heart muscle disease, vascular disorder, and cancer, to obtain an excellent effect. 

1. A thiazole-based compound represented by Chemical Formula 1:

wherein,

R1 is R and R′ are the same or different for each other, and independently selected from the group consisting of hydrogen atom, halogen atom, C1-C5

alkyl, alkyloxy, phenyloxy, nitro, cyano, alkoxycarbonyl, and C3-C6 cycloalkyl, n is 0, 1, or 2,

R2 is X is halogen atom.
 2. The compound according to claim 1, represented by following Chemical Formula 2 or Chemical Formula 3:

wherein, R and R′ are the same or different for each other, and independently selected from the group consisting of hydrogen atom, halogen atom, C1-C5

alkyl, alkyloxy, phenyloxy, nitro, cyano, alkoxycarbonyl, and C3-C6 cycloalkyl, n is 0, 1, or 2, X is halogen atom.
 3. The compound according to claim 1, selected from the group consisting of: [2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2-fluoro-5-nitrophenyl)acetamide hydrochloride]; N-(2-chloro-4-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; N-(3-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-fluorophenyl)acetamide hydrochloride; N-(5-chloro-2-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; N-(4-chloro-2-fluorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; N-(2-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-p-tolylacetamide hydrochloride; N-(4-cyanophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-phenylacetamide hydrochloride; N-(4-bromophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3-fluoro-4-methoxyphenyl)acetamide hydrochloride; N-(4-chlorophenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3,5-dichlorophenyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-ethylphenyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methylbenzyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methylphenethyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3,4-difluorobenzyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-fluorophenethyl)acetamide hydrochloride; N-(2-bromo-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; N-(4-ethoxyphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-isopropylphenyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-nitrophenyl)acetamide hydrochloride; N-(4-decylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; ethyl 3-(2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamido)benzoate hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-hexylphenyl)acetamide hydrochloride; N-(4-butoxyphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; ethyl 4-(2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamido)benzoate hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-hexylphenyl)acetamide hydrochloride; N-(4-(cyanomethyl)phenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; N-(4-butylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-phenoxyphenyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,6-dichloro-4-(trifluoromethyl)phenyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,3,4-trifluorophenyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(4-methoxy-2-methylphenyl)acetamide hydrochloride; N-(3,5-bis(trifluoromethyl)phenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,3,5,6-tetrachlorophenyl)acetamide hydrochloride; N-(3-chloro-4-methylphenyl)-2-(2-(diaminomethyleneamino)thiazole-4-yl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(2,6-dichloro-4-(trifluoromethoxy)phenyl)acetamide hydrochloride; 2-(2-(diaminomethyleneamino)thiazole-4-yl)-N-(3-fluoro-4-methoxyphenyl)acetamide hydrochloride; 2-(4-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-yl)thiazole-2-yl)guanidine hydrochloride; 2-(5-(4-fluorobenzyl)-4-methylthiazole-2-yl)guanidine hydrochloride; 2-(4-(4-chlorophenyl)thiazole-2-yl)guanidine hydrochloride; 2-(4-(4-fluorophenyl)thiazole-2-yl)guanidine hydrochloride; 2-(4-(2,4-difluorophenyl)thiazole-2-yl)guanidine hydrochloride; 2-(4-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-yl)thiazole-2-yl)guanidine hydrochloride; 2-(4-(biphenyl-4-yl)thiazole-2-yl)guanidine hydrochloride; 2-(4-(naphthalene-2-yl)thiazole-2-yl)guanidine hydrochloride; 2-(4-p-tolylthiazole-2-yl)guanidine hydrobromide; 2-(4-(4-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(2-chlorophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(2-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(4-nitrophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(2,4-dimethoxyphenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(2-fluoro-4-methoxyphenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(2,4-dichlorophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-phenylthiazole-2-yl)guanidine hydrobromide; 2-(4-(4-bromophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-m-tolylthiazole-2-yl)guanidine hydrobromide; 2-(4-(3-fluorophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(2-fluorophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(3-(trifluoromethyl)phenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(3-bromophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(4-ethylphenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(3-chlorophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(4-nitrophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(3,4-dichlorophenyl)thiazole-2-yl)guanidine hydrobromide; 2-(4-(2,5-difluorophenyl)thiazole-2-yl)guanidine hydrobromide; and 2-(4-(3,5-bis(trifluoromethyl)phenyl)thiazole-2-yl)guanidine hydrobromide.
 4. A composition for inhibiting T-type calcium channel containing the thiazole-based compound according to claim 1 or pharmaceutically acceptable salt thereof as an active ingredient.
 5. A composition for treating or preventing at least one disease selected from pain, epilepsy, hypertension, angina pectoris, heart muscle disease, vascular disorder, and cancer, wherein the composition contains the thiazole-based compound according to claim 1 or pharmaceutically acceptable salt thereof as an active ingredient.
 6. The composition according to claim 5, additionally containing at least one additive selected from the group consisting of drugs, diluents, fillers, expanders, wetting agents, disintegrants, and surfactants.
 7. A food or food additive containing the thiazole-based compound according to claim 1 or pharmaceutically acceptable salt thereof. 